The long-term objective of this project is the discovery and development of novel high affinity and selective nociceptin opioid receptor (NOP) agonists that can be advanced into human clinical testing for alcoholism. While NOP agonists have not yet been clinically investigated for alcohol dependence, there is significant pharmacological evidence showing dysregulation of the nociceptin system by chronic alcohol intake linked to increased alcohol seeking and anxiety-like behavior. Indeed, nociceptin/orphanin FQ (N/OFQ), the endogenous peptide agonist of the NOP receptor reduces the rewarding actions of alcohol and prevents reinstatement of alcohol seeking in laboratory animals. Importantly, N/OFQ is shown to have anti-anxiety-like and anti-stress-like activity, attenuates alcohol withdrawal symptoms and can reverse the behavioral effects of stress in relapse models of alcohol addiction. These preclinical pharmacological findings strongly support the NOP receptor system as a promising target for treating alcohol addiction and suggest that small- molecule, drug-like NOP receptor agonists may be particularly suitable as a promising approach for treating the various aspects of alcohol addiction (craving, withdrawal and relapse). In Phase 1 of this project, novel classes of NOP agonists were designed, synthesized, and optimized for their potency and selectivity versus other opioid receptors using state-of- the-art medicinal chemistry approaches of rational drug design and computer-aided structure-based drug design. From this effort, a selected NOP agonist showed significant inhibition of alcohol preference in a mouse model of alcohol conditioned place preference, thus validating the pharmacological hypothesis that NOP agonists reduce the rewarding effects of alcohol. The Phase II project proposes to continue the lead optimization of novel NOP agonists with emphasis on improving their suitability as drug candidates for advancement into human clinical trials.